Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes.

Lowe Syndrome (LS) is a condition due to mutations in the gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient's OCRL1 variants (OCRL1).

Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex.

Lowe syndrome is an X-linked condition characterized by congenital cataracts, neurological abnormalities and kidney malfunction. This lethal disease is caused by mutations in the OCRL1 gene, which encodes for the phosphatidylinositol 5-phosphatase Ocrl1. While in the past decade we witnessed substantial progress in the identification and characterization of LS patient cellular phenotypes, many of these studies have been performed in knocked-down cell lines or patient's cells from accessible cell types such as skin fibroblasts, and not from the organs affected.

Ciliopathies: the trafficking connection.

The primary cilium (PC) is a very dynamic hair-like membrane structure that assembles/disassembles in a cell-cycle-dependent manner and is present in almost every cell type. Despite being continuous with the plasma membrane, a diffusion barrier located at the ciliary base confers the PC properties of a separate organelle with very specific characteristics and membrane composition. Therefore, vesicle trafficking is the major process by which components are acquired for cilium formation and maintenance.

Ubiquitin: not just for proteasomes anymore.

Ubiquitin is a small protein that can be covalently linked to itself or other proteins, either as single ubiquitin molecules or as chains of polyubiquitin. Addition of ubiquitin to a target protein requires a series of enzymatic activities (by ubiquitin-activating, -conjugating and -ligating enzymes). The first function attributed to ubiquitin was the covalent modification of misfolded cytoplasmic proteins, thereby directing proteasome-dependent proteolysis.

The yeast Epsin Ent1 is recruited to membranes through multiple independent interactions.

In addition to its well known role in targeting proteins for proteasomal degradation, ubiquitin (Ub) is also involved in promoting internalization of cell surface proteins into the endocytic pathway. Moreover, putative Ub interaction motifs (UIMs) as well as Ub-associated (UBA) domains have been identified in key yeast endocytic proteins (the epsins Ent1 and Ent2, and the Eps15 homolog Ede1). In this study, we characterized the interaction of Ub with the Ede1 UBA domain and with the UIMs of Ent1.